Amidinoureas for lowering blood pressure

ABSTRACT

This invention describes novel chemical compounds which are 1-amidino-3-phenylureas. The method of preparing these compounds and their pharmaceutical uses is also disclosed.

This is a Division, of application Ser. No. 842,994 filed Oct. 17, 1977which in turn is a continuation of Ser. No. 629,208 filed Nov. 5, 1975(abandoned) which in turn is continuation-in-part of Ser. No. 379,773filed July 16, 1973, now abanoned.

DESCRIPTION AND PREFERRED EMBODIMENTS

This invention described a class of novel chemical compounds whichcomprises a urea moiety which is substituted in the 1-position by anamidino group in the 3-position with a substituted phenyl ring thusforming 1-amidino-3-substitutedphenylureas. This invention alsodescribes the non-toxic pharmaceutically acceptable salts; the method ofpreparing these compounds; and their pharmaceutical uses.

The novel compounds of this invention are described by the structuralformula I ##STR1## where: R is hydrogen or

loweralkyl;

R₂ is halo;

R₄ is hydrogen,

halo or

loweralkyl;

R₆ is hydrogen,

halo,

loweralkoxy,

nitro,

loweralkylsulfonyl or

haloloweralkyl; and

the non-toxic acid addition salts thereof.

In the descriptive portions of this invention, the following definitionsapply:

The term "loweralkyl" refers to a loweralkyl hydrocarbon groupcontaining from 1 to about 6 carbon atoms which may be straight chainedor branched.

The term "loweralkoxy" signifies an alkoxy group containing from 1 toabout 6 carbon atoms which may be straight chained or branched.

Compounds of this invention which are preferred are described by thegeneral formula I

where:

R is hydrogen or

loweralkyl;

R₂ is halo;

R₄ is hydrogen,

halo or

loweralkyl; and

R₆ is hydrogen or

halo.

The more preferred compounds of this invention include those compounds

where:

R is hydrogen,

methyl or

ethyl;

R₂ is chloro,

bromo or

fluoro;

R₄ is hydrogen,

chloro,

bromo,

fluoro,

methyl or

ethyl; and

R₆ is hydrogen,

chloro,

bromo or

fluoro.

The most preferred compounds are those disclosed

where:

R is hydrogen or

methyl;

R₂ is chloro or

bromo;

R₄ is hydrogen,

chloro,

bromo or

methyl; and

R₆ is hydrogen,

chloro or

bromo.

It is well known in the pharmacological arts that non-toxic acidaddition salts of pharmacologically active amine compounds do not differin activities from their free base. The salts merely provide aconvenient solubility factor.

The amines of this invention may be readily converted to their non-toxicaddition salts by customary methods in the art. The non-toxic salts ofthis invention are those salts the acid component of which ispharmacologically acceptable in the intended dosages; such salts wouldinclude those prepared from inorganic acids, organic acids, higher fattyacids, high molecular weight acids, etc., and include such as:

    ______________________________________                                        hydrochloric acids,                                                                          propionic acids,                                                                           phthalic acid,                                    hydrobromic acids,                                                                           malic acid,  stearic acid,                                     sulfuric acid, succinic acid,                                                                             oleic acid,                                       nitric acids,  glycolic acid,                                                                             abietic acid,                                     phosphoric acid,                                                                             lactic acid, etc.                                              methane sulfonic acid,                                                                       salicylic acid,                                                benzenesulfonic acid,                                                                        benzoic acid,                                                  acetic acids,  nicotinic acid,                                                ______________________________________                                    

Representative compounds of this invention which are particularly usefulare as follows:

1-amidino-3-(2,6-dichlorophenyl)urea

1-amidino-3-(2-chloro-6-bromophenyl)urea

1-amidino-3-(2-chloro-6-fluorophenyl)urea

1-amidino-3-(2-bromo-6-fluorophenyl)urea

1-amidino-3-(2,6-dibromophenyl)urea

1-amidino-3-(2,6-difluorophenyl)urea

1-amidino-3-(2,4-dichlorophenyl)urea

1-amidino-3-(2-chloro-4-bromophenyl)urea

1-amidino-3-(2-chloro-4-fluorophenyl)urea

1-amidino-3-(2-bromo-4-fluorophenyl)urea

1-amidino-3-(2-bromo-4-chlorophenyl)urea

1-amidino-3-(2,4-dibromophenyl)urea

1-amidino-3-(2,4-difluorophenyl)urea

1-amidino-3-(2-chloro-4-methylphenyl)urea

1-amidino-3-(2-chloro-4-ethylphenyl)urea

1-amidino-3-(2-bromo-4-methylphenyl)urea

1-amidino-3-(2-bromo-4-ethylphenyl)urea

1-amidino-3-(2-fluoro-4-methylphenyl)urea

1-amidino-3-(2-fluoro-4-ethylphenyl)urea

1-amidino-3-(2,4,6-trichlorophenyl)urea

1-amidino-3-(2,6-dichloro-4-bromophenyl)urea

1-amidino-3-(2,6-dichloro-4-fluorophenyl)urea

1-amidino-3-(2,6-dichloro-4-methylphenyl)urea

1-amidino-3-(2,6-dichloro-4-ethylphenyl)urea

1-amidino-3-(2,4-dichloro-6-bromophenyl)urea

1-amidino-3-(2,4-dichloro-6-fluorophenyl)urea

1-amidino-3-(2,4-dichloro-6-methylphenyl)urea

1-amidino-3-(2,4-dichloro-6-ethylphenyl)urea

1-amidino-3-(2-chloro-4-chloro-4-bromo-6-methylphenyl)urea

1-amidino-3-methyl-3-(2,6-dichlorophenyl)urea

1-amidino-3-methyl-3-(2,6-dichlorophenyl)urea

1-amidino-3-methyl-3-(2-chloro-6-bromophenyl)urea

1-amidino-3-methyl-3-(2-chloro-6-fluorophenyl)urea1-amidino-3-methyl-3-(2,4-dichlorophenyl)urea

1-amidino-3-methyl-3-(2-chloro-4-bromophenyl)urea

1-amidino-3-methyl-3-(2-bromo-4-chlorophenyl)urea

1-amidino-3-methyl-3-(2-chloro-4-methylphenyl)urea

1-amidino-3-methyl-3-(2-bromo-4-methylphenyl)urea

1-amidino-3-methyl-3-(2,4,6-trichlorophenyl)urea

1-amidino-3-methyl-3-(2,6-dichloro-4-methylphenyl)urea

1-amidino-3-methyl-3-(2,4-dichloro-6-methylphenyl)urea

1-amidino-3-methyl-3-(2-chloro-4-bromo-6-methylphenyl)urea

1-amidino-3-methyl-3-(2,6-dichlorophenyl)urea

1-amidino-3-methyl-3-(2,4-dichlorophenyl(urea

1-amidino-3-methyl-3-(2,6-dichloro-4-methylphenyl)urea

1-amidino-3-methyl-3-(2,4-dichloro-6-methylphenyl)urea

1-amidino-3-methyl-3-(2-chloro-4-bromo-6-methylphenyl)urea

The compounds of this invention may be prepared by the following generalsynthesis:

Condensation of a substitutedphenyl isocyanate (prepared from an anilineand phosg ne in the customary manner) with guanidine results in a1-substitutedphenyl-3-amidinourea. The reaction is carried out in apolar media using solvents such as alcohol, tetrahydrofuran, etc. It isconvenient to carry out the reaction by preparing the isocyanate in thereaction media and then forming guanidine in situ by hydrolyzingguanidine carbonate with base condensation of the isocyanate takes placewhen the guanidine forms and the amidinourea compound results. ##STR2##

These compounds may also be prepared by degradation of the correspondingbiguanide. When a 1-substitutedphenylbiguanide compound is hydrolyzed inacid at raised temperatures then the resultant product is1-substitutedphenyl-3-amidinourea. This reaction is preferably carriedout using hydrochloric acid and the reaction time and reactiontemperature will of course depend on the particular biguanide used andthe concentration of the acid present. In general, the more concentratedacids will not require high temperatures or long periods of reactiontime. ##STR3##

When it is desired to have R substitution, the starting material ofcourse will be an aniline having N-alkyl substitution. Reaction withphosgene results in the aniline acid chloride which is then reacted withthe guanidine to prepare the amidinourea. ##STR4##

The starting anilines are either known, may be prepared by knowntechniques or reference to the preparation is shown. Thus, chlorinationor bromination of an acetanilide or aniline may be carried out in aceticacid, or in the presence of a small amount of iodine dissolved in aninert solvent such as carbon tetrachloride. A solution of chlorine orbromine is then added while the temperature is held near 0° C.iodination may also be carried out by known methods using iodinemonochloride (CII).

Alkylation may be carried out on an acetanilide using an alkyl halideand aluminum chloride under Friedel-Crafts conditions to obtain desiredalkyl substitution.

Nitration may be carried out using fuming nitric acid at about 0° C.

A nitro compound may be hydrogenated to the corresponding amine whichmay then be diazotized and heated in an alcohol medium to form thealkoxy compound.

An amino compound may also be diazotized to the diazonium fluoroboratewhich is then thermally decomposed to the fluoro compound. Diazotizationfollowed by a Sandmeyer type reaction may yield the bromo, chloro oriodo compound.

When an amino compound is diazotized followed by reaction with potassiumethylxanthate and then hydrolyzed, the mercapto compound results. Thisin turn may be alkylated to the alkylthio group which is then oxidizedto the corresponding alkylisulfonyl substituent.

A chloro, bromo or iodo compound may also be reacted withtrifluoromethyliodide and copper power at about 150° C. indimethylformamide to obtain a trifluoromethyl compound [TetrahedronLetters:47, 4095 (1959)].

A hlao compound may also be reacted with cuprous methanesulfinate inquinoline at about 150° C. to obtain a methylsulfonyl compound.

Reactions may also be carried out on the substituted anilines whichwould result in di- and tri-substituted anilines.

Reactions may also be carried out at other stages of synthesis dependingon the substitutents present and the substituents desired and variouscombination of the foregoing reactions will be determined by one skilledin the art in order that the desired product results. Thus, aphenylamidinourea may be halogenated or nitracted as above, etc.

The biguanide starting materials are also either known, may be preparedby known procedures or may be prepared by the following generalsynthesis:

Condensation of cyanoguanide and an aniline in the presence of anequimolar amount of a mineral acid results in the correspondingphenylbiguanide. ##STR5##

This reaction is preferably carried out on the aniline salt either in apolar media or neat and using increased temperatures. The appropriatelysubstituted product may be prepared by the reactions above when theseare also carried out on the biguanide.

The compounds of this invention have a useful degree of gastricanti-secretory activity and are effective in reducing the volume and theacidity of the gastric fluid in humans and mammals. Further, thesecompounds produce a considerable spasmolytic action on thegastrointestinal musculature, i.e., they reduce the peristaltic actionof the gastrointestinal musculature which is manifested by a delay ingastric emptying time. It should further be noted that these compoundsare also characterized by their low acute oral toxicity.

In particular the amidinoureas as herein described are useful in thetreatment of such gastrointestinal disorders and diseases as duodenalulcer and peptic ulcer.

The instant compounds may be used alone or in combination with otherknown antacids such as aluminum hydroxide, magnesium hydroxide,magnesium trisilicate, aluminum glycinate, calcium carbonate and thelike.

The compounds of this invention posses blood-pressure loweringactivities and are also useful as antihypertensive agents.

For all these purposes, the amidinoureas of this invention can benormally administered orally or parenterally. Orally they may beadministered as tablets, aqueous or oily suspension, dispersible powdersor granules, emulsions, hard or soft capsules, or syrups or elixirs.Parenterally they may be administered as a salt in solution which pH isadjusted to physiologically accepted values. Aqueous solutions arepreferred.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, preserving agents and the like, in order toprovide a pharmaceutically elegant and palatable preparation.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of gastrointestinal disease conditions or symptoms, such asduodenal and peptic ulcer, and in the alleviation of hypertensivedisorders. In general, the daily dose can be between about 0.25 mg/kgand 50 mg/kg (preferably in the range of 0.5-10 mg/kg/day), bearing inmind, of course, that in selecting the appropriate dosage in anyspecific case, consideration must be given to the patient's weight,general health, age, and other factors which may influence response tothe drug.

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit reactions that can becorrelated with activity in humans. These tests involve such factors asthe effect of the amidinoureas on gastric secretion, their spasmolyticeffect, their mydriatic effect and deterioration of their toxicity. Ithas been found that the compounds of this invention when tested in theabove variet of situations show a marked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 4-8 hours, and water is given ad lib.The rats are selected at random and separated into groups of 10. Theanimals are treated intraduodenally (I.D.) with the test compound or thevehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 4 hourspostdrug administration, the stomach removed and its contents areassayed for volume, pH and total acids.

A second gastric secretion test is carried out on the dog. This isoutlined in the Handbook of Physiology, Section 6: Alimentary Canal,Volume II: Secretion. American Physiology Society, Washington, D.C.,1967.

It has been found that the compounds of this invention when subjected tothe above gastric secretion tests display marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and are standard tests used todetermine anti-secretory properties.

To determine the anti-ulcer effectiveness the following test isemployed: Male Wistar rats(130-150 grams) are fasted for 24 hours, thengiven reserpine at 5 mg/kg i.p. Twenty-four hours later, the stomachsare removed and examined for ulceration. Ulcers are graded on a 0-4scale and the number of ulcers is recorded. Pretreatment with theamidinourea compounds produces a decrease in ulcer grade and the numberof ulcers compared to the control reserpine-treated rats.

Determination of anti-spasmolytic properties can be carried out by theprocedure as outlined by D. A. Brodie and S. K. Kundrats in theirarticle entitled "Effect of Drugs on Gastric Emptying in Rats", Fed.Proc. 24:714 (1965).

Mydriasis is detected by the procedure of R. A. Turner, ScreeningMethods in Pharmacology, Academic Press, New York, and London, pp.174-5, 1965. Acute toxicity is calculated according to the standardLitchfield-Wilcoxon procedure.

In view of the results of these tests, the pharmacological data clearlyindicates that the amidinoureas of this invention can be considered tobe active gastric anti-secretory and anti-spasmolytic agents which aresubstantially free of anti-cholinergic side effects and having a lowtoxicity.

Tests in animals have also been carried out to show the ability ofcompounds of this invention to inhibit reactions that can be correlatedwith hypertensive effects in humans. One such test is outlined byJacques de Champlain, Lawrence R. Krahoff and Julius Axelrod inCirculation Research XXIII:479 (1968). This testing method is known tocorrelate well with hypertensive activity in humans and is a standardtest used to determine anti-hypertensive properties. In view of theresults of this test, the amidinoureas of this invention can beconsidered to be active antihypertensive agents.

The following are detailed examples with show the properties of thecompounds of this invention. They are to be construed as illustrationsof said compounds and not as limitations thereof.

Example 1 1-Amidino-3-(2,6-dichloro-4-methylphenyl)urea

To 17.6 g (0.1 mole) of 2,6-dichloro-4-methylaniline in 300 ml ofanhydrous benzene is added 325 ml of 12.5% phosgene in benzene (0.395mole). The reaction mixture is refluxed for 2 hours and the benzene isstripped off under reduced pressure to get rid of the phosgene and hteresidue purified by distillation. This2,6-dichloro-4-methylphenyl-isocyanate is then dissolved in 50 ml oftetrahydrofuran and added dropwise to a hetergeneous mixture of 11.2 gof potassium hydroxide and 18 g of guanidine carbonate in 250 mltetrahydrofuran. This mixture is stirred for 8 hours and then 35 ml ofconc. hydrochloric acid is added followed by 40 ml of conc. sodiumhydroxide solution maintaining the mixture cool in a cold water bath.The mixture is next poured in 1500 ml of water and the tetrahydrofuranis removed under diminished pressure. The mixture is extracted withehter which is then dried and evaporated to dryness to obtain1-amidino-3-(2,6 -dichloro-4-methylphenyl)urea.

The hydrochloride solution is prepared by dissolving the free base inmethanol and adding a methanolic hydrogen chloride solution to form thesalt. The volume of the mixture is concentrated, ether added and1-amidino-3-(2,5-dichloro-4-methylphenyl)urea hydrochloride is filteredoff.

When 2,6-dichloro-4-methylaniline in the above procedure is replaced bythe aniline of Table I, below, then the corresponding products of TableII, below, are prepared.

                  TABLE I                                                         ______________________________________                                        o-chloroaniline 2-bromo-6-fluoroaniline                                       o-bromoaniline  2-chloro-6-methoxyaniline                                     o-fluoroaniline 2-chloro-6-ethoxyaniline                                      o-iodoaniline   2-bromo-6-methoxyaniline                                      2,4-dichloroaniline                                                                           2-fluoro-6-methoxyaniline                                     2,4-dibromoaniline                                                                            2-chloro-6-nitroaniline                                       2,4-difluoroaniline                                                                           2-bromo-6-nitroaniline                                        2-chloro-4-bromoaniline                                                                       2-fluoro-6-nitroaniline                                       2-chloro-4-fluoroaniline                                                                      2-chloro-6-methylsulfonylaniline                              2-bromo-4-chloroaniline                                                                       2-bromo-6-methylsulfonylaniline                               2-bromo-4-fluoroaniline                                                                       2-fluoro-6-methylsulfonylaniline                              2-fluoro-4-chloroaniline                                                                      2-chloro-6-trifluoromethylaniline                             2-fluoro-4-bromoaniline                                                                       2-bromo-6-trifluoromethylaniline                              2-chloro-4-methylaniline                                                                      2-fluoro-6-trifluoromethylaniline                             2-chloro-4-ethylaniline                                                                       2,4,6-trichloroaniline                                        2-chloro-4-propylaniline                                                                      2,6-dichloro-4-bromoaniline                                   2-chloro-4-i-propylaniline                                                                    2,6-dichloro-4-fluoroaniline                                  2-chloro-4-butylaniline                                                                       2,4-dichloro-6-bromoaniline                                   2-chloro-4-t-butylaniline                                                                     2,4-dichloro-6-fluoroaniline                                  2-chloro-4-pentylaniline                                                                      2,4-dibromo-6-chloroaniline                                   2-chloro-4-hexylaniline                                                                       2,4-difluoro-6-chloroaniline                                  2-chloro-4-heptylaniline                                                                      2,4-difluoro-6-bromoaniline                                   2-bromo-4-methylaniline                                                                       2,6-difluoro-4-chloroaniline                                  2-bromo-4-ethylaniline                                                                        2,6-difluoro-4-bromoaniline                                   2-fluoro-4-methylaniline                                                                      2-chloro-4-bromo-6-fluoroaniline                              2-fluoro-4-ethylaniline                                                                       2,6-dichloro-4-iodoaniline                                    2,6-dichloroaniline                                                                           2,6-dichloro-4-ethylaniline                                   2,6-dibromoaniline                                                                            2,6-dichloro-4-propylaniline                                  2,6-difluoroaniline                                                                           2,4-difluoro-6-ethylaniline                                   2-chloro-6-bromoaniline                                                                       2,4-dimethyl-6-chloroaniline                                  2-chloro-6-fluoroaniline                                                                      2,4-dimethyl-6-bromoaniline                                   2,4-dimethyl-6-fluoroaniline                                                  2,4-diethyl-6-chloroaniline                                                   2,4-diethyl-6-fluoroaniline                                                   2-chloro-4-methyl-6-fluoroaniline                                             2-chloro-4-methyl-6-bromoaniline                                              2-chloro-4-ethyl-6-fluoroaniline                                              2-chloro-4-ethyl-6-bromoaniline                                               2,4-dichloro-6-nitroaniline                                                   2,4-dichloro-6-methoxyaniline                                                 2,4-dichloro-6-methylsulfonylaniline                                          2,4-dichloro-6-trifluoromethylaniline                                         2-chloro-4-methyl-6-nitroaniline                                              2-chloro-4-methyl-6-methoxyaniline                                            2-chloro-4-methyl-6-methylsulfonylaniline                                     2-chloro-4-methyl-6-trifluoromethylaniline                                    2,4-difluoro-6-trifluoromethylaniline                                     

                  TABLE II                                                        ______________________________________                                        1-amidino-3-(o-chlorophenyl)urea                                              1-amidino-3-(o-bromophenyl)urea                                               1-amidino-3-(o-fluorophenyl)urea                                              1-amidino-3-(o-iodophenyl)urea                                                1-amidino-3-(2,4-dichlorophenyl)urea                                          1-amidino-3-(2,4-dibromophenyl)urea                                           1-amidino-3-(2,4-difluorophenyl)urea                                          1-amidino-3-(2-chloro-4-bromophenyl)urea                                      1-amidino-3-(2-chloro-4-fluorophenyl)urea                                     1-amidino-3-(2-bromo-4-chlorophenyl)urea                                      1-amidino-3-(2-bromo-4-fluorophenyl)urea                                      1-amidino-3-(2-fluoro-4-chlorophenyl)urea                                     1-amidino-3-(2-fluoro-4-bromophenyl)urea                                      1-amidino-3-(2-chloro-4-methylphenyl)urea                                     1-amidino-3-(2-chloro-4-ethylphenyl)urea                                      1-amidino-3-(2-chloro-4-propylphenyl)urea                                     1-amidino-3-(2-chloro-4-i-propylphenyl)urea                                   1-amidino-3-(2-chloro-4-butylphenyl)urea                                      1-amidino-3-(2-chloro-4-t-butylphenyl)urea                                    1-amidino-3-(2-chloro-4-pentylphenyl)urea                                     1-amidino-3-(2-chloro-4-hexylphenyl)urea                                      1-amidino-3-(2-chloro-4-heptylphenyl)urea                                     1-amidino-3-(2-bromo-4-methylphenyl)urea                                      1-amidino-3-(2-bromo-4-ethylphenyl)urea                                       1-amidino-3-(2-fluoro-4-methylphenyl)urea                                     1-amidino-3-(2-fluoro-4-ethylphenyl)urea                                      1-amidino-3-(2,6-dichlorophenyl)urea                                          1-amidino-3-(2,6-dibromophenyl)urea                                           1-amidino-3-(2,6-difluorophenyl)urea                                          1-amidino-3-(2-chloro-6-bromophenyl)urea                                      1-amidino-3-(2-chloro-6-fluorophenyl)urea                                     1-amidino-3-(2-bromo-6-fluorophenyl)urea                                      1-amidino-3-(2-chloro-6-methoxyphenyl)urea                                    1-amidino-3-(2-chloro-6-ethoxyphenyl)urea                                     1-amidino-3-(2-bromo-6-methoxyphenyl)urea                                     1-amidino-3-(2-fluoro-6-methoxyphenyl)urea                                    1-amidino-3-(2-chloro-6-nitrophenyl)urea                                      1-amidino-3-(2-bromo-6-nitrophenyl)urea                                       1-amidino-3-(2-fluoro-6-nitrophenyl)urea                                      1-amidino-3-(2-chloro-6-methylsulfonylphenyl)urea                             1-amidino-3-(2-bromo-6-methylsulfonylphenyl)urea                              1-amidino-3-(2-fluoro-6-methylsulfonylphenyl)urea                             1-amidino-3-(2-chloro-6-trifluoromethylphenyl)urea                            1-amidino-3-(2-bromo-6-trifluoromethylphenyl)urea                             1-amidino-3-(2-fluoro-6-trifluoromethylphenyl)urea                            1-amidino-3-(2,4,6-trichlorophenyl)urea                                       1-amidino-3-(2,6-dichloro-4-bromophenyl)urea                                  1-amidino-3-(2,6-dichloro-4-fluorophenyl)urea                                 1-amidino-3-(2,4-dichloro-6-bromophenyl)urea                                  1-amidino-3-(2,4-dichloro-6-fluorophenyl)urea                                 1-amidino-3-(2,4-dibromo-6-chlorophenyl)urea                                  1-amidino-3-(2,4-difluoro-6-chlorophenyl)urea                                 1-amidino-3-(2,4-difluoro-6-bromophenyl)urea                                  1-amidino-3-(2,6-difluoro-4-chlorophenyl)urea                                 1-amidino-3-(2,6-difluoro-4-bromophenyl)urea                                  1-amidino-3-(2-chloro-4-bromo-6-fluorophenyl)urea                             1-amidino-3-(2,6-dichloro-4-iodophenyl)urea                                   1-amidino-3-(2,6-dichloro-4-ethylphenyl)urea                                  1-amidino-3-(2,6-dichloro-4-propylphenyl)urea                                 1-amidino-3-(2,4-dimethyl-6-chlorophenyl)urea                                 1-amidino-3-(2,4-dimethyl-6-bromophenyl)urea                                  1-amidino-3-(2,4-dimethyl-6-fluorophenyl)urea                                 1-amidino-3-(2,4-diethyl-6-chlorophenyl)urea                                  1-amidino-3-(2,4-diethyl-6-fluorophenyl)urea                                  1-amidino-3-(2-chloro-4-methyl-6-fluorophenyl)urea                            1-amidino-3-(2-chloro-4-methyl-6-bromophenyl)urea                             1-amidino-3-(2-chloro-4-ethyl-6-fluorophenyl)urea                             1-amidino-3-(2-chloro-4-ethyl-6-bromophenyl)urea                              1-amidino-3-(2,4-dichloro-6-nitrophenyl)urea                                  1-amidino-3-(2,4-dichloro-6-methoxyphenyl)urea                                1-amidino-3-(2,4-dichloro-6-methylsulphonylphenyl)urea                        1-amidino-3-(2,4-dichloro-6-trifluoromethylphenyl)urea                        1-amidino-3-(2-chloro-4-methyl-6-nitrophenyl)urea                             1-amidino-3-(2-chloro-4-methyl-6-methoxyphenyl)urea                           1-amidino-3-(2-chloro-4-methyl-6-methylsulfonylphenyl)urea                    1-amidino-3-(2-chloro-4-methyl-6-trifluoromethylphenyl)urea                   1-amidino-3-(2,4-difluoro-6-trifluoromethylphenyl)urea                        ______________________________________                                    

EXAMPLE 2 1-Amidino-3-(2,6-dichlorophenyl)-3-methylurea

To 17.6 g (0.1 mole) of 2,6-dichloro-N-methylamidino in 300 ml ofanhydrous benzene is added 325 ml of 12.5% phosgene in benzene (0.40mole). The reaction mixture is refluxed for 2 hours and the benzeneremoved under reduced pressure to also eliminate any excess phosgene.The residue is 2,6-dichloro-N-methylamidino acid chloride. This is thendissolved in 50 ml of tetrahydrofuran and added dropwise to aheterogeneous mixture of 11.2 g of potassium hydroxide and 18 g ofguanidine carbonate in 250 ml of tetrahydrofuran. This mixture isstirred for about 10 hours, acidified with conc. hydrochloric and thenbacified with conc. sodium hydroxide solution while maintaining themixture in an HCl both. This is then poured into 1500 ml of water andthe THF removed under diminished pressure. The mixture is extracted withether, which is then dried and evaporated to dryness to obtain1-amidino-3-(2,6-dichlorophenyl)-3-methylurea.

The hydrochloride salt is prepared by dissolving the free base inmethanol and adding methanolic HCl to form the salt. The addition ofether accelerates the precipitation of the salt which is filtered off toobtain 1-amidino-3-(2,6-dichlorophenyl)-3-methylurea hydrochloride.

When 2,6-dichloro-N-methylaniline in the above example is replaced bythe anilines of Table I, below, then the corresponding products of TableII, below, are prepared.

                                      TABLE I                                     __________________________________________________________________________    N-methyl-o-chloroaniline      N-methyl-2-chloro-6-methoxyaniline              N-methyl-o-bromoaniline       N-methyl-2-fluoro-6-methoxyaniline              N-methyl-0-fluoroaniline      N-methyl-2-chloro-6-nitroaniline                N-methyl-o-iodoaniline        N-methyl-2-fluoro-6-nitroaniline                N-methyl-2,4-dichloroaniline  N-methyl-2-chloro-6-methylsulfonylaniline       N-methyl-2,4-dibromoaniline   N-methyl-2-fluoro-6-methylsulfonylaniline       N-methyl-2,4-difluoroaniline  N-methyl-2-chloro-6-trifluoromethylaniline      N-methyl-2-chloro-4-bromoaniline                                                                            N-methyl-2-fluoro-6-trifluoromethylaniline      N-methyl-2-chloro-4-fluoroaniline                                                                           N-methyl-2,4,6-trichloroaniline                 N-methyl-2-bromo-4-chloroaniline                                                                            N-methyl-2,6-dichloro-4-bromoaniline            N-methyl-2-bromo-4-fluoroaniline                                                                            N-methyl-2,6-dichloro-4-fluoroaniline           N-methyl-2-fluoro-4-chloroaniline                                                                           N-methyl-2,4-dichloro-6-bromoaniline            N-methyl-2-fluoro-4-bromoaniline                                                                            N-methyl-2,4-dichloro-6-fluoroaniline           N-methyl-2-chloro-4-methylaniline                                                                           N-methyl-2,4-dibromo-6-chloroaniline            N-methyl-2-chloro-4-ethylaniline                                                                            N-methyl-2,4-difluoro-6-chloroaniline           N-methyl-2-chloro-4-propylaniline                                                                           N-methyl-2,4-difluoro-6-bromoaniline            N-methyl-2-chloro-4-i-propylaniline                                                                         N-methyl-2,6-difluoro-6-chloroaniline           N-methyl-2-chloro-4-butylaniline                                                                            N-methyl-2,6-difluoro-6-bromoaniline            N-methyl-2-chloro-4-t-butylaniline                                                                          N-methyl-2-chloro-4-bromo-6-fluoroaniline       N-methyl-2-chloro-4-pentylaniline                                                                           N-methyl-2,6-dichloro-4-iodoaniline             N-methyl-2-chloro-4-hexylaniline                                                                            N-methyl-2,6-dichloro-4-methylaniline           N-methyl-2-chloro-4-heptylaniline                                                                           N-methyl-2,6-dichloro-4-ethylaniline            N-methyl-2-bromo-4-methylaniline                                                                            N-methyl-2,6-dichloro-4-propylaniline           N-methyl-2-bromo-4-ethylaniline                                                                             N-methyl-2,4-dimethyl-6-chloroaniline           N-methyl-2-fluoro-4-methylaniline                                                                           N-methyl-2,4-dimethyl-6-bromoaniline            N-methyl-2-fluoro-4-ethylaniline                                                                            N-methyl-2,4-dimethyl-6-fluoroaniline           N-methyl-2,6-dibromoaniline   N-methyl-2,4-diethyl-6-chloroaniline            N-methyl-2,6-difluoroaniline  N-methyl-2,4-diethyl-6-fluoroaniline            N-methyl-2-chloro-6-bromoaniline                                                                            N-methyl-2-chloro-4-methyl-6-fluoroaniline      N-methyl-2-chloro-6-fluoroaniline                                                                           N-methyl-2-chloro-4-methyl-6-bromoaniline       N-methyl-2-bromo-6-fluoroaniline                                                                            N-methyl-2-chloro-4-ethyl-6-fluoroaniline       N-methyl-2-chloro-4-ethyl-bromoaniline                                        N-methyl-2,4-dichloro-6-nitroaniline                                          N-methyl-2,4-dichloro-6-methoxyaniline                                        N-methyl-2,4-dichloro-6-methylsulfonylaniline                                 N-methyl-2,4-dichloro-6-trifluoromethylaniline                                N-methyl-2-chloro-4-methyl-6-nitroaniline                                     N-methyl-2-chloro-4-methyl-6-methoxyaniline                                   N-methyl-2-chloro-4-methyl-6-methylsulfonylaniline                            N-methyl-2-chloro-4-methyl-6-trifluoromethylaniline                           N-methyl-2,4-difluoro-6-trifluoromethylaniline                                N-ethyl-2,4-dichloroaniline                                                   N-ethyl-2,4-difluoroaniline                                                   N-ethyl-2-chloro-4-fluoroaniline                                              N-ethyl-2-fluoro-4-chloroaniline                                              N-ethyl-2-chloro-4-methylaniline                                              N-ethyl-2-chloro-4-ethylaniline                                               N-ethyl-2-fluoro-4-methylaniline                                              N-ethyl-2-fluoro-4-ethylaniline                                               N-methyl-2,6-dichloroaniline                                                  N-methyl-2,6-difluoroaniline                                                  N-methyl-2-fluoro-6-trifluoromethylaniline                                    N-methyl-2,6-dichloro-4-fluoroaniline                                         N-methyl-2,6-dichloro-4-methylaniline                                         N-methyl-2,4-dichloro-6-fluoroaniline                                         N-methyl-2,4-difluoro-6-chloroaniline                                         N-methyl-2,4-dimethyl-6-chloroaniline                                         N-methyl-2,4-dimethyl-6-fluoroaniline                                         N-methyl-2-chloro-4-methyl-6-fluoroaniline                                    N-propyl-2,4-dichloroaniline                                                  N-propyl-2,4-difluoroaniline                                                  N-propyl-2-chloro-4-fluoroaniline                                             N-propyl-2-fluoro-4-chloroaniline                                             N-propyl-2-chloro-4-methylaniline                                             N-propyl-2-chloro-4-ethylaniline                                              N-propyl-2-fluoro-4-methylaniline                                             N-propyl-2-fluoro-4-ethylaniline                                              N-propyl-2,6-dichloroaniline                                                  N-propyl-2,6-difluoroaniline                                                  N-butyl-2,4-dichloroaniline                                                   N-butyl-2,4-difluoroaniline                                                   N-butyl-2-chloro-4-methylaniline                                              N-butyl-2-fluoro-4-methylaniline                                              __________________________________________________________________________

                  TABLE II                                                        ______________________________________                                        1-amidino-3-(o-chlorophenyl)-3-methylurea                                     1-amidino-3-(o-bromophenyl)-3-methylurea                                      1-amidino-3-(o-fluorophenyl)-3-methylurea                                     1-amidino-3-(o-iodophenyl)-3-methylurea                                       1-amidino-3-(2,4-dichlorophenyl)-3-methylurea                                 1-amidino-3-(2,4-dibromophenyl)-3-methylurea                                  1-amidino-3-(2,4-difluorophenyl)-3-methylurea                                 1-amidino-3-(2-chloro-4-bromophenyl)-3-methylurea                             1-amidino-3-(2-chloro-4-fluorophenyl)-3-methylurea                            1-amidino-3-(2-bromo-4-chlorophenyl)-3-methylurea                             1-amidino-3-(2-bromo-4-fluorophenyl)-3-methylurea                             1-amidino-3-(2-fluoro-4-chlorophenyl)-3-methylurea                            1-amidino-3-(2-fluoro-4-bromophenyl)-3-methylurea                             1-amidino-3-(2-chloro-4-methylphenyl)-3-methylurea                            1-amidino-3-(2-chloro-4-ethylphenyl)-3-methylurea                             1-amidino-3-(2-chloro-4-propylphenyl)-3-methylurea                            1-amidino-3-(2-chloro-4-i-propylphenyl)-3-methylurea                          1-amidino-3-(2-chloro-4-butylphenyl)-3-methylurea                             1-amidino-3-(2-chloro-4-t-butylphenyl)-3-methylurea                           1-amidino-3-(2-chloro-4-pentylphenyl)-3-methylurea                            1-amidino-3-(2-chloro-4-hexylphenyl)-3-methylurea                             1-amidino-3-(2-chloro-4-heptylphenyl)-3-methylurea                            1-amidino-3-(2-bromo-4-methylphenyl)-3-methylurea                             1-amidino-3-(2-bromo-4-ethylphenyl)-3-methylurea                              1-amidino-3-(2-fluoro-4-methylphenyl)-3-methylurea                            1-amidino-3-(2-fluoro-4-ethylphenyl)-3-methylurea                             1-amidino-3-(2,6-dibromophenyl)-3-methylurea                                  1-amidino-3-(2,6-difluorophenyl)-3-methylurea                                 1-amidino-3-(2-chloro-6-bromophenyl)-3-methylurea                             1-amidino-3-(2-chloro-6-fluorophenyl)-3-methylurea                            1-amidino-3-(2-bromo-6-fluorophenyl)-3-methylurea                             1-amidino-3-(2-chloro-6-methoxyphenyl)-3-methylurea                           1-amidino-3-(2-fluoro-6-methoxyphenyl)-3-methylurea                           1-amidino-3-(2-chloro-6-nitrophenyl)-3-methylurea                             1-amidino-3-(2-fluoro-6-nitrophenyl)-3-methylurea                             1-amidino-3-(2-chloro-6-methylsulfonylphenyl)-3-methylurea                    1-amidino-3-(2-fluoro-6-methylsulfonylphenyl)-3-methylurea                    1-amidino-3-(2-chloro-6-trifluoromethylphenyl)-3-methylurea                   1-amidino-3-(2-fluoro-6-trifluoromethylphenyl)-3-methylurea                   1-amidino-3-(2,4,6-trichlorophenyl)-3-methylurea                              1-amidino-3-(2,6-dichloro-4-bromophenyl)-3-methylurea                         1-amidino-3-(2,6-dichloro-4-fluorophenyl)-3-methylurea                        1-amidino-3-(2,4-dichloro-6-bromophenyl)-3-methylurea                         1-amidino-3-(2,4-dichloro-6-fluorophenyl)-3-methylurea                        1-amidino-3-(2,4-dibromo-6-chlorophenyl)-3-methylurea                         1-amidino-3-(2,4-difluoro-6-chlorophenyl)-3-methylurea                        1-amidino-3-(2,4-difluoro-6-bromophenyl)-3-methylurea                         1-amidino-3-(2,6-difluoro-4-chlorophenyl)-3-methylurea                        1-amidino-3-(2,6-difluoro-4-bromophenyl)-3-methylurea                         1-amidino-3-(2-chloro-4-bromo-6-fluorophenyl)-3-methylurea                    1-amidino-3-(2,6-dichloro-4-iodophenyl)-3-methylurea                          1-amidino-3-(2,6-dichloro-4-methylphenyl)-3-methylurea                        1-amidino-3-(2,6-dichloro-4-ethylphenyl)-3-methylurea                         1-amidino-3-(2,6-dichloro-4-propylphenyl)-3-methylurea                        1-amidino-3-(2,4-dimethyl-6-chlorophenyl)-3-methylurea                        1-amidino-3-(2,4-dimethyl-6-bromophenyl)-3-methylurea                         1-amidino-3-(2,4-dimethyl-6-fluorophenyl)-3-methylurea                        1-amidino-3-(2,4-diethyl-6-chlorophenyl)-3-methylurea                         1-amidino-3-(2,4-diethyl-6-fluorophenyl)-3-methylurea                         1-amidino-3-(2-chloro-4-methyl-6-fluorophenyl)-3-methylurea                   1-amidino-3-(2-chloro-4-methyl-6-bromophenyl)-3-methylurea                    1-amidino-3-(2-chloro-4-ethyl-6-fluorophenyl)-3-methylurea                    1-amidino-3-(2-chloro-4-ethyl-6-bromophenyl)-3-methylurea                     1-amidino-3-(2,4-dichloro-6-nitrophenyl)-3-methylurea                         1-amidino-3-(2,4-dichloro-6-methoxyphenyl)-3-methylurea                       1-amidino-3-(2,4-dichloro-6-methylsulfonylphenyl)-3-methylurea                1-amidino-3-(2,4-dichloro-6-trifluoromethylphenyl)-3-methylurea               1-amidino-3-(2-chloro-4-methyl-6-nitrophenyl)-3-methylurea                    1-amidino-3-(2-chloro-4-methyl-6-methoxyphenyl)-3-methylurea                  1-amidino-3-(2-chloro-4-methyl-6-methylsulfonylphenyl)-3-                     methylurea                                                                    1-amidino-3-(2-chloro-4-methyl-6-trifluoromethylphenyl)-3-                    methylurea                                                                    1-amidino-3-(2,4-difluoro-6-trifluoromethylphenyl)-3-methylurea               1-amidino-3-(2,4-dichlorophenyl)-3-ethylurea                                  1-amidino-3-(2,4-difluorophenyl)-3-ethylurea                                  1-amidino-3-(2-chloro-4-fluorophenyl)-3-ethylurea                             1-amidino-3-(2-fluoro-4-chlorophenyl)-3-ethylurea                             1-amidino-3-(2-chloro-4-methylphenyl)-3-ethylurea                             1-amidino-3-(2-chloro-4-ethylphenyl)-3-ethylurea                              1-amidino-3-(2-fluoro-4-methylphenyl)-3-ethylurea                             1-amidino-3-(2-fluoro-4-ethylphenyl)-3-ethylurea                              1-amidino-3-(2,6-dichlorophenyl)-3-methylurea                                 1-amidino-3-(2,6-difluorophenyl)-3-methylurea                                 1-amidino-3-(2-fluoro-6-trifluoromethylphenyl)-3-methylurea                   1-amidino-3-(2,6-dichloro-4-fluorophenyl)-3-methylurea                        1-amidino-3-(2,6-dichloro-4-methylphenyl)-3-methylurea                        1-amidino-3-(2,4-dichloro-6-fluorophenyl)-3-methylurea                        1-amidino-3-(2,4-difluoro-6-chlorophenyl)-3-methylurea                        1-amidino-3-(2,4-dimethyl-6-chlorophenyl)-3-methylurea                        1-amidino-3-(2,4-dimethyl-6-fluorophenyl)-3-methylurea                        1-amidino-3-(2-chloro-4-methyl-6-fluorophenyl)-3-methylurea                   1-amidino-3-(2,4-dichlorophenyl)-3-propylurea                                 1-amidino-3-(2,4-difluorophenyl)-3-propylurea                                 1-amidino-3-(2-chloro-4-fluorophenyl)-3-propylurea                            1-amidino-3-(2-fluoro-4-chlorophenyl)-3-propylurea                            1-amidino-3-(2-chloro-4-methylphenyl)-3-propylurea                            1-amidino-3-(2-chloro-4-ethylphenyl)-3-propylurea                             1-amidino-3-(2-fluoro-4-methylphenyl)-3-propylurea                            1-amidino-3-(2-fluoro-4-ethylphenyl)-3-propylurea                             1-amidino-3-(2,6-dichlorophenyl)-3-propylurea                                 1-amidino-3-(2,6-difluorophenyl)-3-propylurea                                 1-amidino-3-(2,4-dichlorophenyl)-3-butylurea                                  1-amidino-3-(2,4-difluorophenyl)-3-butylurea                                  1-amidino-3-(2-chloro-4-methylphenyl)-3-butylurea                             1-amidino-3-(2-fluoro-4-methylphenyl)-3-butylurea                             ______________________________________                                    

EXAMPLE 3 1-Amidino-3-(2,6-dichlorophenyl)urea

A quantity of 20 g of 1-(2,6-dichlorophenyl)biguanide is added to 200 mlof 10% hydrochloric acid and the mixture is refluxed for 3 hours. Thereaction mixture is then filtered hot and then chilled. The materialwhich separates is then filtered off and recrystallized fromisopropanol/water to obtain 1-amidino-3-(2,6-dichlorophenyl)ureahydrochloride.

The free base is prepared by dissolving the salt in 200 ml of water andadding a 10% sodium hydroxide solution until alkaline. The reactionmixture is then extracted with chloroforms which is dried and evaporatedto dryness to obtain 1-amidino-3-(2,6-dichlorophenyl)urea.

When the biguanides of Table I, below, are used in the above example inplace of 1-(2,6-dichlorophenyl)biguanide then the corresponding productof Table II is obtained.

                                      TABLE I                                     __________________________________________________________________________    1-(o-chlorophenyl)biguanide                                                                     1-(2,6-difluorophenyl)biguanide                             1-(o-bromophenyl)biguanide                                                                      1-(2-chloro-6-bromophenyl)biguanide                         1-(o-fluorophenyl)biguanide                                                                     1-(2-chloro-6-fluorophenyl)biguanide                        1-(2,4-dichlorophenyl)biguanide                                                                 1-(2-chloro-6-methoxyphenyl)biguanide                       1-(2,4-difluorophenyl)biguanide                                                                 1-(2-chloro-6-nitrophenyl)biguanide                         1-(2-chloro-4-bromophenyl)biguanide                                                             1-(2,4,6-trichlorophenyl)biguanide                          1-(2-chloro-4-fluorophenyl)biguanide                                                            1-(2,6-dichloro-4-fluorophenyl)biguanide                    1-(2-bromo-4-chlorophenyl)biguanide                                                             1-(2,4-dichloro-6-fluorophenyl)biguanide                    1-(2-fluoro-4-chlorophenyl)biguanide                                                            1-(2,4-difluoro-6-chlorophenyl)biguanide                    1-(2-chloro-4-methylphenyl)biguanide                                                            1-(2,4-difluoro-6-bromophenyl)biguanide                     1-(2-chloro-4-ethylphenyl)biguanide                                                             1-(2,6-difluoro-4-chlorophenyl)biguanide                    1-(2-chloro-4-bromophenyl)biguanide                                                             1-(2-chloro-4-bromo-6-fluorophenyl)                                           biguanide                                                   1-(2-fluoro-4-methylphenyl)biguanide                                                            1-(2,6-dichloro-4-ethylphenyl)biguanide                     1-(2-fluoro-4-ethylphenyl)biguanide                                                             1-(2,6-dichloro-4-methylphenyl)biguanide                    1-(2,6-dibromophenyl)biguanide                                                                  1-(2,6-difluoro-4-methylphenyl)biguanide                    1-(2,4-dimethyl-6-chlorophenyl)biguanide                                      1-(2,4-dimethyl-6-bromophenyl)biguanide                                       1-(2,4-dimethyl-6-fluorophenyl)biguanide                                      1-(2,4-diethyl-6-chlorophenyl)biguanide                                       1-(2,4-diethyl-6-fluorophenyl)biguanide                                       1-(2-chloro-4-methyl-6-fluorophenyl)biguanide                                 1-(2-chloro-4-ethyl-6-fluorophenyl)biguanide                                  1-(2,4-dichloro-6-methoxyphenyl)biguanide                                     1-(2,4-dichloro-6-trifluoromethylphenyl)biguanide                             1-(2,4-difluoro-6-trifluoromethylphenyl)biguanide                             1-methyl-1-(2,4-dichlorophenyl)biguanide                                      1-methyl-1-(2,4-difluorophenyl)biguanide                                      1-methyl-1-(2-chloro-4-bromophenyl)biguanide                                  1-methyl-1-(2-chloro-4-iodophenyl)biguanide                                   1-methyl-1-(2-bromo-4-chlorophenyl)biguanide                                  1-methyl-1-(2-fluoro-4-chlorophenyl)biguanide                                 1-methyl-1-(2-chloro-4-methylphenyl)biguanide                                 1-methyl-1-(2-chloro-4-ethylphenyl)biguanide                                  1-methyl-1-(2-fluoro-4-methylphenyl)biguanide                                 1-methyl-1-(2-fluoro-4-ethylphenyl)biguanide                                  1-methyl-1-(2,6-dichlorophenyl)biguanide                                      1-methyl-1-(2,6-dibromophenyl)biguanide                                       1-methyl-1-(2,6-difluorophenyl)biguanide                                      1-methyl-1-(2-chloro-6-bromophenyl)biguanide                                  1-methyl-1-(2-chloro-6-fluorophenyl)biguanide                                 1-methyl-1-(2,4,6-trichlorophenyl)biguanide                                   1-methyl-1-(2,6-dichloro-4-fluorophenyl)biguanide                             1-methyl-1-(2,4-difluoro-6-chlorophenyl)biguanide                             1-methyl-1-(2,6-dichloro-4-methylphenyl)biguanide                             1-methyl-1-(2,6-difluoro-4-methylphenyl)biguanide                             1-methyl-1-(2-chloro-4-bromo-6-fluorophenyl)biguanide                         1-methyl-1-(2,4-dimethyl-6-chlorophenyl)biguanide                             1-methyl-1-(2,4-diethyl-6-chlorophenyl)biguanide                              1-methyl-1-(2,4-dimethyl-6-fluorophenyl)biguanide                             1-ethyl-1-(2,4-dichlorophenyl)biguanide                                       1-ethyl-1-(2,4-difluorophenyl)biguanide                                       1-ethyl-1-(2-chloro-4-bromophenyl)biguanide                                   1-ethyl-1-(2-bromo-4-chlorophenyl)biguanide                                   1-ethyl-1-(2-fluoro-4-chlorophenyl)biguanide                                  1-ethyl-1-(2-chloro-4-methylphenyl)biguanide                                  1-ethyl-1-(2-fluoro-4-methylphenyl)biguanide                                  1-ethyl-1-(2-fluoro-4-ethylphenyl)biguanide                                   1-ethyl-1-(2-chloro-4-ethylphenyl)biguanide                                   1-ethyl-1-(2,6-dichlorophenyl)biguanide                                       1-ethyl-1-(2,6-difluorophenyl)biguanide                                       1-ethyl-1-(2,4,6-trichlorophenyl)biguanide                                    1-ethyl-1-(2,4-difluoro-6-chlorophenyl)biguanide                              1-ethyl-1-(2,4-dimethyl-6-chlorophenyl)biguanide                              1-ethyl-1-(2,4-dimethyl-6-fluorophenyl)biguanide                              1-ethyl-1-(2,6-dichloro-4-methylphenyl)biguanide                              1-ethyl-1-(2,6-difluoro-4-methylphenyl)biguanide                              1-propyl-1-(2,4-dichlorophenyl)biguanide                                      1-propyl-1-(2,4-difluorophenyl)biguanide                                      1-propyl-1-(2-chloro-4-methylphenyl)biguanide                                 1-propyl-1-(2-fluoro-4-methylphenyl)biguanide                                 1-propyl-1-(2-fluoro-4-ethylphenyl)biguanide                                  1-propyl-1-(2-chloro-4-ethylphenyl)biguanide                                  1-propyl-1-(2,6-dichlorophenyl)biguanide                                      1-propyl-1-(2,6-diflurophenyl)biguanide                                       __________________________________________________________________________

                  TABLE II                                                        ______________________________________                                        1-amidino-3-(o-chlorophenyl)urea                                              1-amidino-3-(o-bromophenyl)urea                                               1-amidino-3-(o-fluorophenyl)urea                                              1-amidino-3-(2,4-dichlorophenyl)urea                                          1-amidino-3-(2,4-difluorophenyl)urea                                          1-amidino-3-(2-chloro-4-bromophenyl)urea                                      1-amidino-3-(2-chloro-4-fluorophenyl)urea                                     1-amidino-3-(2-bromo-4-chlorophenyl)urea                                      1-amidino-3-(2-fluoro-4-chlorophenyl)urea                                     1-amidino-3-(2-chloro-4-methylphenyl)urea                                     1-amidino-3-(2-chloro-4-ethylphenyl)urea                                      1-amidino-3-(2-chloro-4-bromophenyl)urea                                      1-amidino-3-(2-fluoro-4-methylphenyl)urea                                     1-amidino-3-(2-fluoro-4-ethylphenyl)urea                                      1-amidino-3-(2,6-dibromophenyl)urea                                           1-amidino-3-(2,6-difluorophenyl)urea                                          1-amidino-3-(2-chloro-6-bromophenyl)urea                                      1-amidino-3-(2-chloro-6-fluorophenyl)urea                                     1-amidino-3-(2-chloro-6-methoxyphenyl)urea                                    1-amidino-3-(2-chloro-6-nitrophenyl)urea                                      1-amidino-3-(2,4,6-trichlorophenyl)urea                                       1-amidino-3-(2,6-dichloro-4-fluorophenyl)urea                                 1-amidino-3-(2,4-dichloro-6-fluorophenyl)urea                                 1-amidino-3-(2,4-difluoro-6-chlorophenyl)urea                                 1-amidino-3-(2,4-difluoro-6-bromophenyl)urea                                  1-amidino-3-(2,6-difluoro-4-chlorophenyl)urea                                 1-amidino-3-(2-chloro-4-bromo-6-fluorophenyl)urea                             1-amidino-3-(2,6-dichloro-4-ethylphenyl)urea                                  1-amidino-3-(2,6-dichloro-4-methylphenyl)urea                                 1-amidino-3-(2,4-dimethyl-6-chlorophenyl)urea                                 1-amidino-3-(2,4-dimethyl-6-bromophenyl)urea                                  1-amidino-3-(2,4-dimethyl-6-fluorophenyl)urea                                 1-amidino-3-(2,4-diethyl-6-chlorophenyl)urea                                  1-amidino-3-(2,4-diethyl-6-fluorophenyl)urea                                  1-amidino-3-(2-chloro-4-methyl-6-fluorophenyl)urea                            1-amidino-3-(2-chloro-4-ethyl-6-fluorophenyl)urea                             1-amidino-3-(2,4-dichloro-6-methoxyphenyl)urea                                1-amidino-3-(2,4-dichloro-6-trifluoromethylphenyl)urea                        1-amidino-3-(2,4-difluoro-6-trifluoromethylphenyl)urea                        3-methyl-1-(2,4-dichlorophenyl)urea                                           3-methyl-1-(2,4-difluorophenyl)urea                                           3-methyl-1-(2-chloro-4-bromophenyl)urea                                       3-methyl-1-(2-chloro-4-iodophenyl)urea                                        3-methyl-1-(2-bromo-4-chlorophenyl)urea                                       3-methyl-1-(2-fluoro-4-chlorophenyl)urea                                      3-methyl-1-(2-chloro-4-methylphenyl)urea                                      3-methyl-1-(2-chloro-4-ethylphenyl)urea                                       3-methyl-1-(2-fluoro-4-methylphenyl)urea                                      3-methyl-1-(2-fluoro-4-ethylphenyl)urea                                       3-methyl-1-(2,6-dichlorophenyl)urea                                           3-methyl-1-(2,6-dibromophenyl)urea                                            3-methyl-1-(2,6-difluorophenyl)urea                                           3-methyl-1-(2-chloro-6-bromophenyl)urea                                       3-methyl-1-(2-chloro-6-fluorophenyl)urea                                      3-methyl-1-(2,4,6-trichlorophenyl)urea                                        3-methyl-1-(2,6-dichloro-4-fluorophenyl)urea                                  3-methyl-1-(2,4-difluoro-6-chlorophenyl)urea                                  3-methyl-1-(2,6-dichloro-4-methylphenyl)urea                                  3-methyl-1-(2,6-difluoro-4-methylphenyl)urea                                  3-methyl-1-(2-chloro-4-bromo-6-fluorophenyl)urea                              3-methyl-1-(2,4-dimethyl-6-chlorophenyl)urea                                  3-methyl-1-(2,4-diethyl-6-chlorophenyl)urea                                   3-methyl-1-(2,4-dimethyl-6-fluorophenyl)urea                                  3-ethyl-1-(2,4-dichlorophenyl)urea                                            3-ethyl-1-(2,4-difluorophenyl)urea                                            3-ethyl-1-(2-chloro-4-bromophenyl)urea                                        3-ethyl-1-(2-bromo-4-chlorophenyl)urea                                        3-ethyl-1-(2-fluoro-4-chlorophenyl)urea                                       3-ethyl-1-(2-chloro-4-methylphenyl)urea                                       3-ethyl-1-(2-fluoro-4-methylphenyl)urea                                       3-ethyl-1-(2-fluoro-4-ethylphenyl)urea                                        3-ethyl-1-(2-chloro-4-ethylphenyl)urea                                        3-ethyl-1-(2,6-dichlorophenyl)urea                                            3-ethyl-1-(2,6-difluorophenyl)urea                                            3-ethyl-1-(2,4,6-trichlorophenyl)urea                                         3-ethyl-1-(2,4-difluoro-6-chlorophenyl)urea                                   3-ethyl-1-(2,4-dimethyl-6-chlorophenyl)urea                                   3-ethyl-1-(2,4-dimethyl-6-fluorophenyl)urea                                   3-ethyl-1-(2,6-dichloro-4-methylphenyl)urea                                   3-ethyl-1-(2,6-difluoro-4-methylphenyl)urea                                   3-propyl-1-(2,4-dichlorophenyl)urea                                           3-propyl-1-(2,4-difluorophenyl)urea                                           3-propyl-1-(2-chloro-4-methylphenyl)urea                                      3-propyl-1-(2-fluoro-4-methylphenyl)urea                                      3-propyl-1-(2-fluoro-4-ethylphenyl)urea                                       3-propyl-1-(2-chloro-4-ethylphenyl)urea                                       3-propyl-1-(2,6-dichlorophenyl)urea                                           3-propyl-1-(2,6-difluorophenyl)urea                                           ______________________________________                                    

We claim:
 1. A method for lowering blood pressure comprising administering to a patient suffering from hypertension a therapeutically effective amount between 0.5 mg and 500 mg per dosage unit of at least one compound of the formula: ##STR6## where: R is hydrogen;R₂ is chloro orbromo; R₄ is hydrogen,chloro, bromo or methyl; and R₆ is hydrogen,chloro or bromo; and the non-toxic acid addition salts thereof.
 2. A method for lowering blood pressure comprising administering to a patient suffering from hypertension a therapeutically effective amount between 0.5 mg and 500 mg per dosage unit of at least one compound of the formula: ##STR7## where: R is methyl;R₂ is chloro orbromo; R₄ is hydrogen,chloro, bromo or methyl; and R₆ is hydrogen,chloro or bromo; and the non-toxic acid addition salts thereof.
 3. The method according to claim 1 where R₄ is hydrogen.
 4. The method according to claim 1 where R₆ is hydrogen.
 5. The method according to claim 3 wherein R₂ and R₆ are chloro thus forming 1-amidino-3-(2,6-dichlorophenyl)urea.
 6. The method according to claim 3 where R₂ is chloro and R₆ is bromo thus forming 1-amidino-3-(2-chloro-6-bromophenyl)urea.
 7. The method according to claim 3 where R₂ and R₆ are bromo thus forming 1-amidino-3-(2,6-dibromophenyl)urea.
 8. The method according to claim 3 where R₂ is chloro and R₆ is hydrogen thus forming 1-amidino-3-(o-chlorophenyl)urea.
 9. The method according to claim 3 where R₂ is bromo and R₆ is hydrogen thus forming 1-amidino-3-(o-bromophenyl)urea.
 10. The method according to claim 4 where R₂ and R₄ are chloro thus forming 1-amidino-3-(2,4-dichlorophenyl)urea.
 11. The method according to claim 4 where R₂ is chloro and R₄ is bromo thus forming 1-amidino-3-(2-chloro-4-bromophenyl)urea.
 12. The method according to claim 4 where R₂ is chloro and R₄ is methyl thus forming 1-amidino-3-(2-chloro-4-methylphenyl)urea.
 13. The method according to claim 4 where R₂ is bromo and R₄ is chloro thus forming 1-amidino-3-(2-bromo-4-chlorophenyl)urea.
 14. The method according to claim 4 where R₂ and R₄ are bromo thus forming 1-amidino-3-(2,4-dibromophenyl)urea.
 15. The method according to claim 4 where R₂ is bromo and R₄ is methyl thus forming 1-amidino-3-(2-bromo-4-methylphenyl)urea.
 16. The method according to claim 1 where R₂, R₄ and R₆ are chloro thus forming 1-amidino-3-(2,4,6-trichlorophenyl)urea.
 17. The method according to claim 1 where R₂ and R₆ are chloro and R₄ is bromo thus forming 1-amidino-3-(2,6-dichloro-4-bromophenyl)urea.
 18. The method according to claim 1 where R₂ and R₆ are chloro and R₄ is methyl thus forming 1-amidino-3-(2,6-dichloro-4-methylphenyl)urea.
 19. The method according to claim 2 where R₄ is hydrogen.
 20. The method according to claim 2 where R₆ is hydrogen.
 21. The method according to claim 19 where R₂ and R₆ are chloro thus forming 1-amidino-3-methyl-3-(2,6-dichlorophenyl)urea.
 22. The method according to claim 19 where R₂ is chloro and R₆ is bromo thus forming 1-amidino-3-methyl-3-(2-chloro-6-bromophenyl)urea.
 23. The method according to claim 19 where R₂ and R₆ are bromo thus forming 1-amidino-3-methyl-3-(2,6-dibromophenyl)urea.
 24. The method according to claim 19 where R₂ is chloro and R₆ is hydrogen thus forming 1-amidino-3-methyl-3-(o-chlorophenyl)urea.
 25. The method according to claim 19 where R₂ is bromo and R₆ is hydrogen thus forming 1-amidino-3-methyl-3-(o-bromophenyl)urea.
 26. The method according to claim 20 where R₂ and R₄ are chloro thus forming 1-amidino-3-methyl-3-(2,4-dichlorophenyl)urea.
 27. The method according to claim 20 where R₂ is chloro and R₄ is bromo thus forming 1-amidino-3-methyl-3-(2-chloro-4-bromophenyl)urea.
 28. The method according to claim 20 where R₂ is chloro and R₄ is methyl thus forming 1-amidino-3-methyl-3-(2-chloro-4-methylphenyl)urea.
 29. The method according to claim 20 where R₂ is bromo and R₄ is chloro thus forming 1-amidino-3-methyl-3-(2-bromo-4-chlorophenyl)urea.
 30. The method according to claim 20 where R₂ and R₄ are bromo thus forming 1-amidino-3-methyl-3-(2,4-dibromophenyl)urea.
 31. The method according to claim 2 where R₂, R₄ and R₆ are chloro thus forming 1-amidino-3-methyl-3-(2,4,6-trichlorophenyl)urea.
 32. The method according to claim 2 where R₂ and R₆ are chloro and R₄ is bromo thus forming 1-amidino-3-methyl-3-(2,6-dichloro-4-bromophenyl)urea.
 33. The method according to claim 2 where R₂ and R₆ are chloro and R₄ is methyl thus forming 1-amidino-3-methyl-3-(2,6-dichloro-4-methylphenyl)urea. 